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2006 Grant - Jayadev

Presenilins and Microglia in Alzheimer's Disease

Suman Jayadev, M.D.University of WashingtonSeattle, Washington

2006 New Investigator Research Grant

Beta-amyloid is a protein fragment that is a key suspect in Alzheimer pathology. It is produced when it is cut from a larger molecule by two enzymes, gamma-secretase and beta-secretase. The gamma-secretase enzyme is made up of several proteins. Two of these proteins are presenilin 1 and presenilin 2, which are critical for the activity of gamma-secretase.

Mutations in the genes for presenilin 1 and 2 cause rare inherited forms of Alzheimer's disease. Thus, these proteins are key targets for research and development of therapies to slow or prevent the disease. In addition to their role in gamma-secretase, presenilin 1 and 2 are believed to have important roles in inflammation, cell development and cell survival.

Suman Jayadev, M.D., and colleagues have found that presenilin 2 is increased during inflammation in a specialized cell type known as microglial cells. Although microglial cells are found in the brain, they behave as components of the immune system and are important mediators of inflammation. The researchers also found that patients with Alzheimer's disease have increased levels of presenilin 2 in the brain, mostly in non-nerve cells such as microglia.

Dr. Jayadev and colleagues plan to study the role of presenilins in brain inflammation and in the death of nerve cells. Their studies will focus on the role of presenilins in microglial cells and their interactions with other proteins and cells. These studies will be performed using cultured microglial cells, some of which have been modified by genetic methods to reduce or increase expression of the presenilins.